This competitive renewal is submitted under a new grant title to reflect our current focus on vaccine development, which is a logical extension from our studies that evaluated the immune evasion properties of herpes simplex virus types 1 and 2 (HSV-1 and -2) glycoproteins C (gC) and E (gE). Our approach will be to further define the contributions of HSV-1 and -2 gC and gE to immune evasion from antibody and complement and to immunize with gC and gE proteins to produce antibodies that bind to immune evasion domains on gC and gE and block their functions. In Aim 1 we will evaluate the effects of HSV-1 and -2 gC- and gE-mediated immune evasion on primary and recurrent infections. Our prior studies focused more on HSV-1 than HSV-2;however, we now propose expanding the HSV-2 studies because of its importance to vaccine development. We will evaluate the roles of gC- and gE-mediated immune evasion during primary infection using the murine flank and vaginal models, and during recurrent infection using the guinea pig vaginal model. In Aim 2 we will compare protection from glycoprotein D (gD-1 or gD-2) subunit vaccines at mucosal and epidermal sites and evaluate the impact of HSV-1 and -2 gC- and gE-mediated immune evasion on vaccine efficacy at these sites. We will use murine vaginal and flank models to address whether gD subunit vaccines are more effective at protecting mucosal (female genitalia) than epidermal (male genitalia) sites. These experiments address whether anatomical differences between genders explains the GlaxoSmithKline gD-2 subunit vaccine trial results that reported protection in women but not men. We will also examine the contributions of gC and gE immune evasion to reducing vaccine efficacy at mucosal and epidermal sites. In Aim 3 we will evaluate HSV-1 and -2 gC and gE immunogens that produce antibodies that bind to gC and gE and block their immune evasion functions as a novel approach to prevent immune evasion. Many human pathogens have evolved mechanisms to evade host immunity. Preventing immune evasion may be a critical step in developing the next generation of vaccines. HSV gC and gE are ideal targets since these glycoproteins contribute to virulence and are expressed on the surface of the virion and infected cell. Immunizing to produce blocking antibodies that disrupt gC and gE functions may greatly improve the effectiveness of HSV vaccines.